Mechanism of sleep regulation by SIK3

SIK3对睡眠的调节机制

基本信息

批准号：
10570655
负责人：
David Menassah Raizen
金额：
$ 5.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10570655
关键词：
Acute Adipocytes Adipose tissue Affect Afferent Neurons African-American Graduate Student Animal Model Animals Behavior Control Biochemical Biomedical Research CRISPR/Cas technology Caenorhabditis elegans Cell Nucleus Cells Charge Chloride Channels Complement Couples Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Disease Drowsiness Endocrine Family member Fatty acid glycerol esters Future Genes Genetic Screening Goals Grant High Prevalence Histamine Histone Deacetylase Homeostasis Homologous Gene Imaging Device Individual Knowledge Link Mammals Measures Mediating Mentors Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Movement Nematoda Neuraxis Neuroendocrine Cell Neurons Neurosciences Nuclear Import Oxidants Paraquat Parents Patients Peripheral Pharmacogenetics Phenotype Phosphorylation Phosphotransferases Phylogenetic Analysis Process Publishing ROS1 gene Reactive Oxygen Species Regulation Reporting Research Research Activity Research Personnel Research Project Grants Resistance Role STK11 gene Science Signal Transduction Site Sleep Sleep Disorders Sleeplessness Superoxide Dismutase Talents Technical Expertise Techniques Testing Tissues Training Transgenic Organisms Triglycerides Underrepresented Students Work antioxidant enzyme base calcium indicator career development catalase computerized tools conditional knockout experimental study fatty acid oxidation genetic approach innovation mutant overexpression parent grant pre-doctoral relating to nervous system salt-inducible kinase sleep behavior sleep regulation tool tool development upstream kinase

项目摘要

Project Summary – PARENT APPLICATION The high prevalence of coexistent sleep and metabolic disorders suggest that these processes are integrated at the molecular level, but mechanisms of this integration are unknown. The recent finding that the AMPK family member SIK3 is a phylogenetically conserved sleep drive regulator combined with our preliminary data showing both reduced sleep and elevated energy stores in animals mutant for the C. elegans SIK homolog kin- 29, suggests that SIKs are key nodes connecting sleep and energy homeostasis. The model motivating this proposal is that SIKs are responsive to the energy level in particular neurons; low energy (i.e. low ATP levels) result in the movement of SIK into the nucleus where, via phosphorylation of a class II HDAC it de-represses genes that signal to promote sleep and energy reserve mobilization. We will test this model using the nematode Caenorhabditis elegans and with the following hypotheses: (1) Cellular energy charge is lower under conditions of increased sleep drive. (2) KIN-29/SIK signals under conditions of low energy to mobilize energy stores and restore cellular ATP levels and sleep. (3) KIN-29/SIK functions acutely in metabolically-responsive sensory neurons that regulate the sleep-inducing ALA and RIS neurons; It functions in the same neurons to regulate fat stores. (4) KIN-29/SIK sleep-promoting activity is controlled by nuclear import, which is regulated by the upstream kinases LKB1 and PKA. Finally, (5) we will pursue an exploratory aim by performing a pilot genetic screen to discover new genes that are required for the reduced sleep phenotype of kin-29 mutants. Experiments in aims 1-4 will illuminate the molecular and cellular mechanism by which SIKs function to regulate animal sleep and energetic stores. Aim 5, in which we will identify new sleep genes, will provide a bridge into the next set of hypotheses regarding mechanisms of sleepiness. Lessons gained from the nematode can motivate focused experiments in mammals, and will inform our understanding of patients with disorders of sleep regulation.

项目摘要 - 家长申请睡眠和代谢紊乱共存的高患病率表明这些过程是整合的 AMPK 是在分子水平上进行的，但这种整合的机制尚不清楚。结合我们的初步数据，家族成员 SIK3 是系统发育上保守的睡眠驱动调节因子显示线虫 SIK 同源基因突变体动物的睡眠减少和能量储存增加 29，表明 SIK 是连接睡眠和能量稳态的关键节点，该模型促进了这一点。提议是 SIK 对特定神经元的能量水平有反应；导致 SIK 移动到细胞核中，通过 II 类 HDAC 的磷酸化，它会解除抑制我们将使用促进睡眠和能量储备动员的基因来测试该模型。 (1) 细胞能量消耗较低 (2)低能量条件下KIN-29/SIK信号动员能量 (3) KIN-29/SIK 在代谢反应中发挥敏锐的作用调节睡眠诱导 ALA 和 RIS 神经元的感觉神经元 (4) KIN-29/SIK促睡眠活性受核输入控制，受调控最后，(5) 我们将通过进行试点来实现探索性目标。基因筛选以发现 kin-29 突变体睡眠表型减少所需的新基因。目标 1-4 中的实验将阐明 SIK 发挥作用的分子和细胞机制目标 5（我们将在其中识别新的睡眠基因）将提供调节动物睡眠和能量储存的方法。过渡到下一组有关嗜睡机制的假设。线虫可以激发在哺乳动物身上进行集中实验，并将帮助我们了解患有线虫病的患者睡眠调节障碍。